The neurochemical mechanisms that mediate cocaine's effects are not fully understood. The dopamine transporter, located in the caudate nucleus and putamen, is considered an important mediator of cocaine's effects. These regions of primate brain region accumulate the highest levels of cocaine after i.v. administration. However, the other targets of cocaine may also contribute to the effects of the drug, particularly as cocaine maintains self-administration in the absence of the transporter. In order to fully investigate cocaine distribution in the brain, we conducted PET imaging with [11C]cocaine in primate brain. Analysis of the brain images revealed rapid transport of radioactivity into putamen, caudate, thalamus, frontal cortex and cerebellum. Anatomical regions accumulating [11C]cocaine were verified by magnetic resonance imaging (MRI). The caudate and putamen accumulated the highest levels of cocaine. The orbitofrontal cortex, a region not previously identified as a significant target of cocaine, accumulated [11C]cocaine within two minutes after i.v. administration. In contrast to the caudate or putamen, the time-activity curve was significantly different from that of other brain regions. Radioactivity plateaued and remained high for over 70 minutes in this brain region. These results are significant in view of reports by others that glucose metabolism is severely depressed in the orbitofrontal cortex of monkey brain after chronic cocaine administration. Equally compelling, the orbitofrontal cortex has also been identified as a brain region of significant activity in human subjects after cocaine administration. The binding sites for cocaine in this brain region will be actively investigated in primate and human brain in vitro. Brownell A-L, Livni E, Madras BK. Global approach in modeling of [N-(C-11-methyl] (-)-cocaine] pharmacokinetics in nonhuman